WO2015036507A1

WO2015036507A1 - Use of cabazitaxel in patients with metastatic nsclc progressing after docetaxel-based treatment

Info

Publication number: WO2015036507A1
Application number: PCT/EP2014/069442
Authority: WO
Inventors: Vassilis Georgoulias; Athanasios KOTSAKIS
Original assignee: Aventis Pharma S.A.
Priority date: 2013-09-12
Filing date: 2014-09-11
Publication date: 2015-03-19
Also published as: TW201542201A

Abstract

The invention relates to a compound of formula: which may be in base form or in the form of a hydrate or a solvate, for its use as a medicament in the treatment of metastatic NSCLC, especially for patients who are not catered for by a taxane-based treatment. In particular, the present invention relates to the use of cabazitaxel in the treatment of patients with metastatic NSCLC, who have been previously treated with a docetaxel based regimen.

Description

USE OF CABAZITAXEL IN PATIENTS WITH METASTATIC NSCLC PROGRESSING AFTER

DOCETAXEL-BASED TREATMENT

The present invention relates to the use of cabazitaxel in the treatment of metastatic NSCLC (non small cell lung cancer), especially for patients who are not catered for by a taxane-based treatment. In particular, the present invention relates to the use of cabazitaxel in the treatment of patients with metastatic NSCLC, who have been previously treated with a docetaxel based regimen, an unmet medical need. [Technical problem]

Non small cell lung cancer (NSCLC) represents the second most common type of cancer in both men (after prostate cancer) and women (after breast cancer) in the Western world. It is estimated that approximately 220,000 new cases of lung cancer occurred in 2009 in USA. Both the absolute and relative frequency of lung cancer has risen dramatically. As an example, the age-adjusted death rates from lung cancer were similar to that of pancreatic cancer prior to 1930 for men and prior to 1960 for women. Unfortunately, lung cancer remains by far the most frequent cause of cancer-related death with approximately 159,000 deaths observed in 2009 in USA.

The vast majority of patients are diagnosed with advanced, unresectable disease which remains incurable with a 5-year survival rate of less than 5%, while the 5-year survival for all stages is approximately 15%. For these patients, chemotherapy remains the cornerstone of treatment. Chemotherapy offers an overall survival (OS) benefit with an absolute improvement in survival of 9% at 12 months compared with best supportive care. The American Society of Clinical Oncology (ASCO) recommends cisplatin-based doublets as standard of care for the first line treatment. Platinum-free regimens represent an alternative in patients who cannot tolerate platinum-based treatment.

Docetaxel is considered as one of the most active agents in the treatment of NSCLC. A metaanalysis including data from 2867 patients participating in seven randomized trials compared the treatment effect of docetaxel vs vinca alkaloids. Treatment with docetaxel was associated with a significant, 1 1 % OS improvement (HR 0.89; 95% CI: 0.82- 0.96; p-value< 0.004).

The availability of new active regimens in the first line setting has prompted several investigators to consider second line therapy for patients with advanced NSCLC, since a substantial percentage of patients maintain a good PS (performance status) upon recurrence. On the basis of the results of phase III trials docetaxel, erlotinib, gefitinib, or pemetrexed are considered as "standard" choices for second-line therapy (Shepherd FA et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18: 2095-103; Fossella FV, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18: 2354-62; Hanna N et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22: 1589-97; Shepherd FA et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123-32; Kim ES et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372: 1809-18).

However, despite the increased availability of different drugs, NSCLC remains a devastating disease with median OS which rarely exceeds 12 months. Furthemore, patients often show resistance to first line but also to second line available treatments, as for example to docetaxel treatment. Thus, it is clear that further therapeutic choices are needed.

Thus the technical problem that the invention intends to solve is that of providing a novel second and/or third line therapeutic option for treating metastatic NSCLC, in particular patients with metastatic NSCLC progressing after docetaxel-based treatment.

[Brief description of the invention]

The invention relates to a novel antitumoral pharmaceutical therapeutic use comprising cabazitaxel of fo

The invention also relates to methods of treating patients with metastatic NSCLC comprising administering an effective amount of the antitumoral agent cabazitaxel to said patient.

This antitumoral agent may be in the form of anhydrous base, a hydrate or a solvate, intended for treating metastatic NSCLC, in particular for treating patients who are not catered for by a taxane- based treatment, such as patients who have been previously treated with a docetaxel-based regimen. In some aspects of the invention, cabazitaxel is administered at a dose (defined for each administration) of between 20 and 25 mg/m². Cabazitaxel may be in the form of an acetone solvate. More particularly, the acetone solvate of cabazitaxel contains between 5% and 8% and preferably between 5% and 7% by weight of acetone.

In some aspects of the invention, cabazitaxel may be administered by intravenous infusion at a dose of between 20 and 25 mg/m², this administration cycle of the antitumour agent being repeated at an interval of 3 weeks between each cabazitaxel administration, which interval may be prolonged by 1 to 2 weeks depending on the tolerance to the preceding cabazitaxel administration.

In some embodiments, the effective amount of cabazitaxel produces at least one therapeutic effect improving the survival of the patients selected from the group consisting of:

Improvement of Overall Response Rate (ORR), defined as the proportion of patients with complete or partial response according to RECIST version 1 .1 (Eur J Cancer 2009; 45:

228-47);

Improvement of the Time to response, defined as the time interval between the date of enrollment and the date of the criteria of complete or partial response are met for the first time;

- Improvement of Disease control rate (DCR), defined as the proportion of patients with complete response+ partial response + stable disease;

Improvement of Progression free survival (PFS), defined as the time interval between the date of enrollment and the date of disease progression or death (any cause);

Improvement of Overall survival (OS), defined as the time interval between the date of enrollment and the date of death;

Improvement of the toxicity profile

The present invention also relates to a pharmaceutical composition that treats patients with metastatic NSCLC comprising a clinically proven safe and effective amount of cabazitaxel.

[Description of the invention]

Definitions

Effective amount, as used herein, means an amount of a pharmaceutical compound, such as cabazitaxel, that produces an effect on the cancer to be treated.

- Clinically proven, as used herein, means clinical efficacy results that are sufficient to meet

FDA approval standards.

Patient, as used herein, includes both human and animals. In one embodiment, a patient is a human. Cabazitaxel belongs to the taxoid family and has the formula:

The chemical name of cabazitaxel is 4a-acetoxy-2obenzoyloxy-5p,20-epoxy-i p-hydroxy-7p,10p- dimethoxy-9-oxo-1 1-taxen-13a-yl (2R,3S)-3-ferf-butoxycarbonylamino-2-hydroxy-3- phenylpropionate. Cabazitaxel is synonymously known as (2a,5 ,7 ,10 ,13a)-4-acetoxy-13- ({(2R,3S)-3-[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10- dimethoxy-9-oxo-5,20-epoxytax-1 1-en-2-yl benzoate. This compound and a preparative method thereof is described in WO 96/30355, EP 0817779 B1 and US 5847170, which are hereby incorporated herein by reference. Cabazitaxel may be administered in base form (cf. above formula), or in the form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone solvate, and, more particularly, may be the solvate described in WO 2005/02846. It may be an acetone solvate of cabazitaxel containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means content of acetone/content of acetone+cabazitaxel ^χ 100). An average value of the acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of acetone.

The procedure described below allows the preparation of an acetone solvate of cabazitaxel:

940 ml of purified water are added at 20±5°C (room temperature) to a solution of 207 g of 4a- acetoxy-2a-benzoyloxy-5 ,20-epoxy-i -hydroxy-7 ,10 -dimethoxy-9-oxo-1 1-taxen-13a-yl (2R,3S)-3-ferf-butoxycarbonylamino-2-hydroxy-3-phenylpropionate at about 92% by weight in about 2 litres of acetone, followed by seeding with a suspension of 2 g of 4oacetoxy-2a- benzoyloxy-5 ,20-epoxy-i -hydroxy-7 ,10 -dimethoxy-9-oxo-1 1-taxen-13a-yl (2R,3S)-3-fe/f- butoxycarbonylamino-2-hydroxy-3-phenylpropionate isolated from acetone/water in a mixture of 20 ml of water and 20 ml of acetone. The resulting mixture is stirred for about 10 to 22 hours, and 1.5 litres of purified water are added over 4 to 5 hours. This mixture is stirred for 60 to 90 minutes, and the suspension is then filtered under reduced pressure. The cake is washed on the filter with a solution prepared from 450 ml of acetone and 550 ml of purified water, and then oven-dried at 55°C under reduced pressure (0.7 kPa) for 4 hours. 197 g of 4a-acetoxy-2obenzoyloxy-5p,20- epoxy-i p-hydroxy-7p,10p-dimethoxy-9-oxo-1 1-taxen-13oyl (2R,3S)-3-fe/f-butoxycarbonylamino- 2-hydroxy-3-phenylpropionate acetone containing 0.1 % water and 7.2% acetone (theoretical amount: 6.5% for a stoichiometric solvate) are obtained.

Cabazitaxel may be administered parenterally, such as via intravenous administration. A galenical form of cabazitaxel suitable for administration by intravenous infusion is that in which the cabazitaxel is dissolved in water in the presence of excipients chosen from surfactants, cosolvents, glucose or sodium chloride, etc. For example, a galenical form of cabazitaxel may be prepared by diluting a premix solution of cabazitaxel contained in a sterile vial (80 mg of cabazitaxel + 2 ml of solvent + Polysorbate 80) with a sterile vial containing a solution of 6 ml of water and ethanol (13% by weight of 95% ethanol) in order to obtain 8 ml of a solution ready to be rediluted in a perfusion bag. The concentration of cabazitaxel in this ready-to-redilute solution is about 10 mg/ml. The perfusion is then prepared by injecting the appropriate amount of this ready- to-redilute solution into the perfusion bag containing water and glucose (about 5%) or sodium chloride (about 0.9%).

One aspect of

which may be in base form or in the form of a hydrate or a solvate,

for its use as a medicament in the 2^nd line or 3^rd line treatment of patients with metastatic NSCLC, more particularly where the treated patients are not catered for by a taxane-based treatment, more particularly where the patients treated have been previously treated with a docetaxel-based regimen.

The metastatic NSCLC may be for example a stage IV or stage 1MB NSCLC, more particularly a stage IV NSCLC.

According to the invention, cabazitaxel may be in the form of an acetone solvate. The acetonate solvate may contain between 5% and 8% and preferably between 5% and 7% by weight of acetone.

Accordingly, one aspect of the invention is a method of treating prostate metastatic NSCLC comprising administering to a patient in need thereof an effective amount of cabazitaxel.

Cabazitaxel may be administered at a dose of between 20 and 25 mg/m2, more particularly at a dose of 25 mg/m2. Cabazitaxel may be administered repeatedly according to a protocol that depends on the patient to be treated (age, weight, treatment history, etc.), which can be determined by a skilled physician. In one aspect of the invention, cabazitaxel is administered by perfusion to the patient according to an intermittent program with an interval between each administration of 3 weeks, which may be prolonged by 1 to 2 weeks depending on the tolerance to the preceding administration. Examples of doses for cabazitaxel are given in the "Example" section. The currently recommended dose is 25 mg/m² of cabazitaxel administered as a one-hour infusion.

Another aspect of the invention is a pharmaceutical composition that treats patients with metastatic NSCLC comprising a clinically proven safe and effective amount of cabazitaxel as disclosed here above.

Another aspect of the invention is a method of increasing the survival of a patient with metastatic NSCLC, comprising administering a clinically proven effective amount of cabazitaxel as disclosed here above to the patient.

Example

Objectives of the trial General objectives

To assess the activity of cabazitaxel as second/third line treatment in patients with metastatic NSCLC progressing after docetaxel containing treatment. End-points Primary endpoint

Overall Response Rate (ORR), defined as the proportion of patients with complete or partial response according to RECIST version 1.1 (Eur J Cancer 2009; 45: 228-47). Given that the objective response rate from randomized phase III trials with agents active in the second line setting (docetaxel, eriotinib, gefitinib, or pemetrexed) ranges from about 7-10% (Shepherd FA et al. J Clin Oncol 2000; 18: 2095-103; Fossella FV, et al. J Clin Oncol 2000; 18: 2354-62; Hanna N et al. J Clin Oncol 2004; 22: 1589-97; Shepherd FA et al. N Engl J Med 2005; 353: 123-32; Kim ES et al. Lancet 2008; 372: 1809-18), a minimum objective response rate of 8% will be required in order to consider that the drug is potentially active and requires further evaluation.

Secondary endpoints

i) Time to response, defined as the time interval between the date of enrollment and the date of the criteria of complete or partial response are met for the first time.

ii) Disease control rate (DCR), defined as the proportion of patients with complete responses- partial response + stable disease.

iii) Progression free survival (PFS), defined as the time interval between the date of enrollment and the date of disease progression or death (any cause).

iv) Overall survival (OS), defined as the time interval between the date of enrollment and the date of death,

v) Toxicity profile

Patient selection criteria

Target Population

Patients with stage 1MB with pleural effusion or stage IV NSCLC with documented disease progression during or after completion of docetaxel-based treatment are eligible for the study.

Inclusion Criteria

-Age>18 years old

-Cytologically or histologically documented NSCLC

-Measurable disease according to RECIST v1 .1 (at least one measurable lesion)

-Documented disease progression to previous treatment with docetaxel regimen in 1^st or 2^nd line setting assessed by Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) with at least one visceral or soft-tissue metastatic lesion.

-Brain metastases are allowed, given that are clinically stable and the patient does not present neurologic symptoms. -Previous radiotherapy, either in the adjuvant setting or for the treatment of bone metastases, is allowed provided that the measurable lesions are outside the radiation fields. Patients who were irradiated to≥ 40% of bone marrow are not eligible for the study.

-Patients must have a recent (within 7 days prior to treatment start) biochemical and hematogical assessment as defined by adequate bone marrow (absolute neutrophil count >1 .5 x 10⁹ cells/L, platelets >100 x 10⁹cells/L and hemoglobin≥9 g/dL), liver (AST&ALT≤ 2.5x ULN, total bilirubin within normal range) and renal (serum creatinine < 1.5 x ULN). If creatinine 1.0 - 1.5 x ULN, creatinine clearance will be calculated according to CKD-EPI formula and patients with creatinine clearance <60 mL/min should be excluded) function tests (Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-12).

-Performance status (PS) 0-2 (WHO scale)

-Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

-Before patient enrollment, written informed consent must be given according to ICH/GCP and national/local regulations.

Exclusion Criteria:

-Persistence of clinically relevant treatment-related toxicities from previous chemotherapy or radiotherapy.

-Treatment with other investigational drugs or treatment in another clinical trial within the past four weeks before start of treatment or concomitantly with this trial.

-Other malignancy within the past five years other than basal cell skin cancer or carcinoma in situ of the cervix.

-Patient with reproductive potential not implementing accepted and effective method of contraception

-History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs or to docetaxel

- Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus, hypertension, heart failure≤ NYHA II, history of myocardial infarction within the past 6 months, angina, chronic obstructive pulmonary disease (COPD), serious infections requiring systemic antibiotic therapy (e.g. antimicrobial, antifungal, antiviral)

-Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments)

- Prior surgery, radiation, chemotherapy, within 4 weeks prior to treatment

- Active grade≥2 peripheral neuropathy

- Active grade≥2 stomatitis Study Schedule

Patients will receive cabazitaxel 25 mg/m² intravenously over 1 h on day 1 of each 21 -day cycle. Premedication, consisting of single intravenous doses of an antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent), corticosteroid (dexamethasone 8 mg or equivalent), and histamine H2-antagonist (ranitidine or equivalent) will be administered 30 min or more before cabazitaxel. Antiemetic prophylaxis will be given at physicians' discretion. Treatment will be administered until disease progression, unacceptable toxicity or patient refusal. In case of toxicity, dose reductions should be done according to the protocol below.

Primary prophylaxis with Granulocyte Colony-Stimulating Factor (G-CSF) should be considered in patients with high-risk clinical features (age>65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. In patients with grade 3 or 4 neutropenia or febrile neutropenia, the subsequent cycle will be given with prophylactic administration of G-CSF; in the case of grade 3 or 4 neutropenia or febrile neutropenia despite the administration of G-CSF the subsequent cycle will be administered at the dose of 20 mg/m² of cabazitaxel.

Patients with NSCLC stage IV will be registered at the HORG Clinical Trials Office prior to the start of treatment. After verification of the eligibility criteria, subjects will be enrolled in the trial and will receive treatment.

Treatment duration

Cabazitaxel treatment should be administered until documented disease progression, unacceptable toxicity, or patient refusal.

Withdrawal criteria

Whatever the disease status, the treatment will always be discontinued in case of:

• patient refusal

• excessive toxicity precluding further therapy, according to the responsible physician

• disease progression

After progression, the following treatment will be left to the discretion of the treating physician. Dose modifications

General Rules

Every effort will be made to administer the full dose regimen to maximize dose-intensity. If possible, toxicities should be managed symptomatically. If toxicity occurs, the appropriate therapy will be offered to ameliorate signs and symptoms. All toxicities (any grade) will be recorded.

Dose reduction Dose will be reduced at 20 mg/m² in case of grade 3 or 4 hematologic or non-hematologic toxicity, as described below. Dose re-escalation is not allowed, after dose reduction.

Only one dose reduction will be allowed per patient. If a second dose reduction is required, the patient should be withdrawn from the study.

Chemotherapy Delay

Treatment delay up to 3 days is acceptable. A delay≥ 4 days should be justified (ie, to be reported in the CRF). Treatment may be delayed no more than 2 weeks for the recovery from acute toxicity. In case of treatment delay greater than 2 weeks, the patient should be withdrawn from treatment with cabazitaxel.

Myelosuppression

Table 1 - Chemotherapy dose modifications for hematologic toxicity

^*T temperature

^**Maximum of 2 weeks delay, otherwise the patient will be withdrawn from treatment

- Allergy (Anaphylactic and Hypersensitivity reactions)

Mild: localized cutaneous reaction, o Consider decreasing the rate of infusion until such as: pruritus, flushing, rash. recovery of symptoms, stay at bedside

o Complete cabazitaxel infusion at the initial

planned rate.

Moderate: Generalized pruritus, o Stop cabazitaxel infusion

more severe flushing or rash, mild o Give IV diphenhydramine 50 mg and/or IV dyspnea, hypotension with systolic dexamethasone 10 mg B . >80 mmHg o Once all signs and/or symptoms of

hypersensitivity reaction disappear, cabazitaxel may be re-administered within 24 hours from the interruption, if medically appropriate.

o Re-administer premedication regimen when

cabazitaxel is re-infused more than 3 hours after the interruption

o Administer cabazitaxel over 2 hours for all

subsequent infusions

Severe: bronchospasm, o Stop cabazitaxel infusion

generalized urticaria, hypotension o Give IV diphenhydramine 50 mg and/or IV with systolic B.P. ≤80 mmHg, dexamethasone 10 mg

angioedema. o Add epinephrine or bronchodilators and/or IV

plasma expanders if indicated

o Once all signs and/or symptoms of

hypersensitivity reaction disappear, cabazitaxel may be re-infused within 24 hours from the interruption, if medically appropriate, and whenever possible

o Re-administer premedication regimen when

cabazitaxel is re-infused more than 3 hours after the interruption

o Administer cabazitaxel over 2 hours for all

subsequent infusions

o If a severe reaction recurs, patient will go off

protocol therapy

Anaphylaxis (Grade 4 reaction) Withdraw treatment

Nausea/Vomiting

A prophylactic anti-emetic treatment should be given to the patients in all cycles. The use of metoclopramide is recommended. More aggressive anti-emetic prophylaxis (ie ondansetron, etc.) should be given to the patients who have experienced grade≥3 nausea/vomiting in a preceding cycle. If despite the appropriate medication, grade≥3 nausea/vomiting still occur, reduce the dose of cabazitaxel. If despite dose reduction, nausea/vomiting still occur at grade≥3, the patient should be withdrawn from treatment with cabazitaxel. Diarrhea

No prophylactic treatment for diarrhea is recommended in Cycle 1. However, following the first episode of diarrhea, the patient should be treated with rehydration or antidiarrheal medications as needed. In case of Grade≥ 3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement, delay treatment until improvement or resolution, then reduce the dose. If despite dose reduction, diarrhea still occurs at grade≥3, the patient will be withdrawn from treatment with cabazitaxel.

Stomatitis

If grade 3 stomatitis occurs, cabazitaxel should be withheld until resolution to grade≤1. Treatment may then be resumed, but the dose of cabazitaxel should be reduced for all subsequent doses. In case of grade 4 stomatitis, the patient will be withdrawn from treatment with cabazitaxel.

Peripheral neuropathy

Dose modification should be performed as follows:

o Grade≤1 : No change

o Grade 2: Retreat with reduced dose

o Grade 3: Patient will be withdrawn from treatment with cabazitaxel Liver toxicity

In case of increase of SGOT(AST) and/or SGPT(ALT) to >1 .5 x ULN or bilirubin to >ULN, delay cabazitaxel treatment for up to 2 weeks until SGOT(AST) and/or SGPT(ALT) returned to <1.5 x ULN and bilirubin to≤ULN. Then retreat patient at reduced dose for rest of the treatment. Other Toxic Effects

For any other toxicity grade 2, manage symptomatically, and retreat without dose reduction. If grade 3 or worse toxicity is occurred, cabazitaxel administration should be held (except for alopecia) until recovery to grade 2 and then re-administrate with reduced dose.

Alopecia and nail changes will not require dose modification.

Evaluation of efficacy

Objective tumor response and time of progression will be measured according to the RECIST criteria (version 1 .1).

Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and - together with other lesions that are denoted as non-target lesions - followed until disease progression.

Methods of measurements The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up.

Clinical Lesions: Clinical lesions will only be considered measurable when they are superficial and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is recommended. If feasible, imaging is preferred.

Chest X-ray: Chest CT is preferred over chest X-ray, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 20 mm on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung.

CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for response assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). While PET scans are not considered adequate to measure lesions, PET-CT scans may be used in order to investigate suspicious lesions or to evaluate differences concerning metabolic activity of the tumor.

(18F-FDG-)PET-scan: Although being a good technique to characterize or evaluate primary pulmonary cancers, including its metastases, the utilization of this technique for objective tumor response should not be considered in this study because lack of reproducibility and poor harmonization of response criteria in NSCLC impede this technology to be an adequate biomarker.

Frequency of tumor re-evaluation

Chest and abdominal CT or MRI and bone scan should be done to assess all TARGET and non- TARGET lesions. A spiral CT acquisition is preferred with slice thickness of 5mm.

Tumor assessment should be performed every 6 weeks (1 cycle)

To ensure comparability the imaging should be performed using identical techniques throughout the study period.

The bone scan will be performed every 6 months except in the case of newly appearing lesions. For patients who withdraw from protocol treatment for reasons other than progression, tumor assessment should be performed every 6 weeks until the first documentation of progression.

Adverse events related to study conditions

The SAE (Serious Adverse Event) reporting period begins with signing of the informed consent. AEs (Adverse Events) should be followed to resolution or stabilization, and reported as SAEs if they become serious. This also applies to patients experiencing AEs that cause interruption or discontinuation of investigational product, or those experiencing AEs that are present at the end of their participation in the study. Such patients should receive post-treatment follow-up as appropriate. If an ongoing AE changes in its severity or in its perceived relationship to study drug, a new AE entry for the event should be completed.

Handling of Serious Adverse Events (SAEs)

A serious AE is any untoward medical occurrence that at any dose:

• results in death,

• is life-threatening (defined as an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetical^ might have caused death if it were more severe),

· requires patient hospitalization or causes prolongation of existing hospitalization,

• results in persistent or significant disability/incapacity,

• is a congenital anomaly/birth defect,

• results in the development of drug dependency or drug abuse,

• is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above). Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization). Occurrences of pregnancy or overdose (regardless of adverse outcome) are considered as events which must be reported as important medical events.

Adverse events classified as "serious" require expeditious handling. Study design

This is a pilot, multi-center, phase II trial of cabazitaxel in patients with stage IV and stage 1MB NSCLC who will progress during or after docetaxel-containing treatment.

The aim of the trial is to confirm that cabazitaxel sustain its activity in patients who will progress during or after docetaxel- containing treatment, to determine whether cabazitaxel could be considered for further investigation in this population in the 2^nd line setting and to evaluate its toxicity profile. A minimum objective response rate of 8% is suitable in order to declare that cabazitaxel is potentially active in this setting and merits to be further evaluated.

40 patients are planned to be enrolled who will progress during or after treatment with docetaxel in the front- or the second-line setting. The study will run in two stages: during the first stage, 25 patients will be enrolled; a minimum of 2 objective responses are required in order to proceed to the second part of the trial.

Adverse events (AEs) and serious adverse events (SAEs) will be analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Results

We investigated the activity of cabazitaxel in patients with metastatic NSCLC progressing under or after docetaxel-based regimens.

Material and Methods: Eligible patients had stage IV NSCLC; measurable disease; ECOG performance status 0-2; up to 2 prior chemotherapy regimens for the treatment of metastatic disease from which one containing docetaxel. Treatment consisted of cabazitaxel (25 mg/m2 iv, every 21 days) until disease progression. G-CSF was administered to the physician's discretion. The primary endpoint was the objective response rate with a planned sample size of 40 eligible patients. A 2-stage design was applied with an interim analysis after enrolment of the first 25 patients (min 2 objectives responses).

Results: At the completion of the first stage (n=25 patients) 30% had squamous cell carcinoma, 52% adenocarcinoma and 18% a low differentiated NSCLC. Three patients received one and 22 patients two prior regimens. Among the 21 evaluable patients, 4 (19%) patients showed partial response, 8 (38%) stable disease [Disease Control Rate=57%] and 9 (43%) progressive disease. The most common adverse events were anemia (54%); lymphopenia (38%); fatigue (35%). Grade 3/4 adverse events were neutropenia: 2/2; lymphopenia: 6/0; anemia: 1/0; thrombocytopenia: 0/1 ; diarrhea: 1/0; fatigue: 1/0. There was no treatment-related death. The estimated median PFS is 2.8 months. Treatment compliance was 94% as 1 patient withdrew due to toxicity (fatigue). 5 cycles delayed (6.2%), 3 due to toxicity and 2 for other reasons. Hematologic toxicity was the reason for dose reduction in 3 patients.

Conclusions: These preliminary results further support that cabazitaxel is active in docetaxel- resistant tumors. Its efficacy in pre-treated patients with NSCLC implies the necessity to explore its role in the treatment algorithm either in the first or second-line setting.

Claims

CLAIMS What is claimed is:

1. Compound of formula

which may be in base form or in the form of a hydrate or a solvate,

for its use as a medicament in the 2^nd line or 3^rd line treatment of patients with metastatic NSCLC.

2. Compound according to claim 1 , where the treated patients are not catered for by a taxane-based treatment.

3. Compound according to claim 1 or 2, where the patients treated have been previously treated with a docetaxel-based regimen.

4. Compound according to any one of claims 1 to 3, where the metastatic NSCLC is a stage IV or stage NIB NSCLC.

5. Compound according to any one of claims 1 to 4, where the metastatic NSCLC is a stage IV NSCLC.

6. Compound according to any one of claims 1 to 5, in the form of an acetone solvate.

7. Compound according to Claim 6, in which the acetone solvate contains between 5% and 8% and preferably between 5% and 7% by weight of acetone.

8. Compound according to any one of claims 1 to 7, administered at a dose of between 20 and 25 mg/m².

9. Compound according to claim 8, administered at a dose of 25 mg/m².

10. Compound according to any one of claims 1 to 9, comprising repeating the administration of such compound as a new cycle every 3 weeks.

11. Compound according to any one of claims 1 to 10, which when administered to a group of patients gives an increased objective response rate.

12. Compound according to claim 1 1 , where the objective response rate is a least of 8%.

13. A pharmaceutical composition comprising a compound as defined in claims 1 to 12.

14. A method of increasing the survival of a patient with metastatic NSCLC, comprising administering a clinically proven effective amount of a compound as defined in any one of claims 1 to 12 to the patient.